The Gl2 subfamily of heterotrimeric G proteins, comprised of the alpha- subunits G-alphal2 and G-alpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. We have discovered a novel and specific interaction between the Gl2 subfamily and the cytoplasmic domain of several members of the cadherin family of cell-surface adhesion proteins. Ga12 or Ga13-binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli (APC) protein required for beta-catenin degradation, expression of mutationally-activated G12 proteins causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily, and reveal a novel link between heterotrimeric G proteins and cellular processes controlling growth and differentiation. In this application, we propose to i) map the key determinants of the Ga12/cadherin interaction, ii) develop reagents that specifically block this protein: protein interaction, and iii) utilize these reagents to elucidate the importance of this interaction in G12- mediated oncogenesis. These studies should not only validate the importance of the Ga12/cadherin interaction as a target in cell proliferative and oncogenesis, but also yield experimental systems that could be exploited to develop specific target-based assays for inhibitor discovery.